This application claims under 35 U.S.C. xc2xa7119(a)-(d) or xc2xa7365(b) of European Patent Application No. 01810503.1 filed May 21, 2001.
The present invention relates to a process for coating articles, wherein the coating comprises a polymer having desirable characteristics regarding adherence to the substrate, durability, softness, hydrophilicity, lubricity, wettability, biocompatibility and permeability. More particular, the present invention relates to a process for coating an article, such as a biomedical material or article, especially a contact lens including an extended-wear contact lens, wherein the coating is composed of at least two individual hydrophilic polymer components. One of those hydrophilic components comprises polymer chains which are covalently bound to the substrate, whereas the second hydrophilic polymer is not covalently bound neither to the surface of the substrate nor to the polymer chains, but is being entrapped with said polymer chains.
Processes for preparing hydrophilic polymeric coatings on an xe2x80x9cinertxe2x80x9d hydrophobic substrate have been disclosed in the prior art. For example, WO 99/57581 discloses to first of all providing the article surface with covalently bound photoinitiator molecules, coating the modified surface with a layer of a polymerizable macromonomer and then subjecting it to a heat or radiation treatment whereby the macromonomer is graft polymerized thus forming the novel article surface. The covalent binding of the photoinitiator molecules to the article surface is created by first subjecting the article surface to a plasma treatment thereby providing the surface with functional groups, and then reacting said functional groups with co-reactive groups of a functional photoinitiator.
Surprisingly, it now has been found that articles, particularly biomedical devices such as contact lenses, with an even improved wettability, water-retention ability and biocompatibility are obtained by first of all providing the bulk material surface with covalently bound photoinitiator molecules, followed by grafting a hydrophilic ethylenically unsaturated macromonomer from the bulk material surface in the presence of a biocompatible hydrophilic polymer being devoid of polymerizable ethylenically unsaturated groups and thereby entrapping said biocompatible hydrophilic polymer within the polymer matrix formed by the polymerization of the macromonomer.
By this process, the macromonomer forms xe2x80x9cbottle-brushxe2x80x9d type tethered xe2x80x9chairyxe2x80x9d chains on the bulk material surface having entangled a biocompatible hydrophilic polymer thereby forming a kind of semi-interpenetrating network (s-IPN) with the polymer chains of the macro-monomer.
The present invention therefore in one aspect relates to a process for coating a material surface comprising the steps of:
(a) providing an inorganic or organic bulk material having covalently bound to its surface initiator moieties for radical polymerization;
(b) graft polymerizing a hydrophilic ethylenically unsaturated macromonomer from the bulk material surface in the presence of a biocompatible hydrophilic polymer being devoid of polymerizable ethylenically unsaturated groups and thereby entrapping said hydrophilic polymer within the polymer matrix formed by the polymerization of the macromonomer.
Suitable bulk materials to be coated according to the invention are, for example, quartz, ceramics, glasses, silicate minerals, silica gels, metals, metal oxides, carbon materials such as graphite or glassy carbon, natural or synthetic organic polymers, or laminates, composites or blends of said materials, in particular natural or synthetic organic polymers or modified biopolymers which are known in large number. Some examples of polymers are polyaddition and polycondensation polymers (polyurethanes, epoxy resins, polyethers, polyesters, polyamides and polyimides); vinyl polymers (polyacrylates, polymethacrylates, polyacrylamides, polymethacrylamides, polystyrene, polyethylene and halogenated derivatives thereof, polyvinyl acetate and polyacrylonitrile); or elastomers (silicones, polybutadiene and polyisoprene).
A preferred group of materials to be coated are those being conventionally used for the manufacture of biomedical devices, e.g. contact lenses, in particular contact lenses for extended wear, which are not hydrophilic per se. Such materials are known to the skilled artisan and may comprise for example polysiloxanes, perfluoroalkyl polyethers, fluorinated poly(meth)acrylates or equivalent fluorinated polymers derived e.g. from other polymerizable carboxylic acids, polyalkyl (meth)acrylates or equivalent alkylester polymers derived from other polymerizable carboxylic acids, or fluorinated polyolefines, such as fluorinated ethylene or propylene, for example tetrafluoroethylene, preferably in combination with specific dioxols, such as perfluoro-2,2-dimethyl-1,3-dioxol. Examples of suitable bulk materials are e.g. lotrafilcon A, neofocon, pasifocon, telefocon, silafocon, fluorsilfocon, paflufocon, elastofilcon, fluorofocon or teflon AF materials, such as teflon AF 1600 or teflon AF 2400 which are copolymers of about 63 to 73 mol % of perfluoro-2,2-dimethyl-1,3-dioxol and about 37 to 27 mol % of tetrafluoroethylene, or of about 80 to 90 mol % of perfluoro-2,2-dimethyl-1,3-dioxol and about 20 to 10 mol % of tetrafluoroethylene.
Another group of preferred materials to be coated are amphiphilic segmented copolymers comprising at least one hydrophobic segment and at least one hydrophilic segment, which are linked through a bond or a bridge member. Examples are silicone hydrogels, for example those disclosed in PCT applications WO 96/31792 and WO 97/49740.
A particular preferred group of materials to be coated comprises organic polymers selected from polyacrylates, polymethacrylates, polyacrylamides, poly(N,N-dimethylacrylamides), polymethacrylamides, polyvinyl acetates, polysiloxanes, perfluoroalkyl polyethers, fluorinated polyacrylates or -methacrylates and amphiphilic segmented copolymers comprising at least one hydrophobic segment, for example a polysiloxane or perfluoroalkyl polyether segment or a mixed polysiloxane/perfluoroalkyl polyether segment, and at least one hydrophilic segment, for example a polyoxazoline, poly(2-hydroxyethylmethacrylate), polyacrylamide, poly(N,N-dimethylacrylamide), polyvinylpyrrolidone polyacrylic or polymethacrylic acid segment or a copolymeric mixture of two or more of the underlying monomers.
The material to be coated may also be any blood-contacting material conventionally used for the manufacture of renal dialysis membranes, blood storage bags, pacemaker leads or vascular grafts. For example, the material to be modified on its surface may be a polyurethane, polydimethylsiloxafle, polytetrafluoroethylene, polyvinylchioride, DACRON(copyright) (a long-chain polyester made from ethylene glycol and tereophthalic acid), SILATIC(copyright) (a flexible inert silicone rubber), or a composite made therefrom.
The form of the material to be coated may vary within wide limits. Examples are particles, granules, capsules, fibres, tubes, films or membranes, preferably moldings of all kinds such as ophthalmic moldings, for example intraocular lenses, artificial cornea or in particular contact lenses.
The bonding of the photoinitiator moieties according to step (a) may be accomplished
(i) according to the methods described in WO 99/57581, where the surface of the bulk material is first of all subjected to a plasma treatment thereby introducing reactive groups at the surface of the surface, followed by reaction of said reactive groups with an initiator moiety bearing co-reactive functional groups, or
(ii) by reaction of certain hetero-bifunctional compounds at the surface of the bulk material said compounds having a first highly reactive functional group, which is able to react with the xe2x80x9cinertxe2x80x9d bulk material surface, and a second functional group for further covalent attachment of the initiator moieties.
Said hetero-bifunctional compound is, for example, a compound of formula 
or xe2x88x92N3xe2x80x83xe2x80x83(2b)
wherein R29 is C1-C4-alkyl, C1-C4-alkoxy, amino, hydroxy, sulfo, nitro, trifluoromethyl or halogen,
g is an integer from 0 to 2,
L1 is a group, which functions as a triggerable precursor for carbene or nitrene formation,
L2 is amino, C1-C4-alkylamino, hydroxy, glycidyl, carboxy or a derivative thereof, isocyanato or isothiocyanato, or is a radical of formula
xe2x80x94[L3]h-(spacer)-L2xe2x80x2xe2x80x83xe2x80x83(1a),
wherein L2xe2x80x2 is amino, C1-C4-alkylamino, hydroxy, carboxy or a derivative thereof, isocyanato, isothiocyanato, xe2x80x94O-glycidyl or xe2x80x94Oxe2x80x94C(O)xe2x80x94(CH2)h1xe2x80x94X2, wherein h1 is from 1 to 4 and X2 is carboxy or a derivative thereof,
L3 is xe2x80x94NHxe2x80x94, xe2x80x94NC1-C6-alkyl-, xe2x80x94Oxe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94C(O)NHxe2x80x94, xe2x80x94NHC(O)NHxe2x80x94, xe2x80x94NHC(O)Oxe2x80x94 or xe2x80x94OC(O)NHxe2x80x94;
(spacer) is linear or branched C1-C200-alkylene which may be substituted by hydroxy and/or interrupted by xe2x80x94Oxe2x80x94 except for C1-alkyl, or is C3-C8-cycloalkylene, C3-C8-cycloalkylene-C1-C6-alkylene, C3-C8-cycloalkylene-C1-C2-alkylene-C3-C8-cycloalkylene or C1-C6-alkylene-C3-C8-cycloalkylene-C1-C6-alkylene; and
h is the number 0 or 1.
L1 in formula (1) is, for example, a group of formula 
wherein R30 is an electron-withdrawing substituent, for example fluorinated C1-C6-alkyl, such as a radical xe2x80x94C2F5 or preferably a radical xe2x80x94CF3.
R29 is preferably C1-C4-alkoxy, nitro, C1-C4-alkyl, hydroxy, amino or sulfo. The variable g is, for example, 1 or preferably 0.
One group of suitable radicals of formula (1) are those wherein L1 is a group 
and g is 0. A further group of suitable radicals of formula (1) are those wherein L1 is a group xe2x80x94N3, and g is 1 or preferably 0.
Throughout the application the terms carboxy derivative, a derivative of carboxy and the like are to be understood as meaning, for example, a lactone, a carboxylic acid anhydride, halide, amide or ester, for example xe2x80x94C(O)Cl, xe2x80x94C(O)NH2, xe2x80x94C(O)C1-C6-alkyl, xe2x80x94C(O)-phenyl or in particular an activated ester such as carboxy having been reacted with an activating agent, for example with N-hydroxy succinimide (NHS) or sulfo-N-hydroxy succinimide. A particularly preferred carboxy derivative is an activated ester of formula 
wherein Ka+ is a cation, for example Na+ or K+.
The term glycidyl means a radical 
The bivalent radicals L3 are always to be understood that the left bond is directed to the phenyl ring and the right bond is directed to the (spacer) radical.
According to one preferred embodiment of the invention, L2 is amino, isocyanato, isothiocyanato, carboxy or a derivative thereof, and in particular amino, isocyanato, carboxy, or an activated carboxylic acid ester as mentioned above.
L3 in formula (1a) is preferably a bivalent group xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94C(O)Oxe2x80x94, xe2x80x94C(O)NHxe2x80x94 or xe2x80x94NHC(O)NHxe2x80x94, and is most preferably a radical xe2x80x94NHxe2x80x94, xe2x80x94C(O)Oxe2x80x94 or xe2x80x94C(O)NHxe2x80x94. h is preferably the number 1.
(spacer) in formula (1a) is preferably linear or branched, optional hydroxy-substituted, C1-C24-alkylene or C4-C160-alkylene which is interrupted by xe2x80x94Oxe2x80x94, more preferably C1-C16-alkylene or C8-C160-alkylene which is interrupted by xe2x80x94Oxe2x80x94 and most preferably C2-C12-alkylene or xe2x80x94(alkxe2x80x2)xe2x80x94Oxe2x80x94(CH2CH2O)18-160xe2x80x94(alkxe2x80x2)xe2x80x94, wherein (alkxe2x80x2) is, for example, C1-C6-alkylene, preferably C1-C4-alkylene more preferable C1-C3-alkylene and in particular 1,2-ethylene. If (spacer) is a cycloalkylene or mixed alkylene/cycloalkylene radical, the meanings and preferences given below for R33 apply.
L2xe2x80x2 is preferably amino, isocyanato, carboxy, a carboxy derivative, or a radical xe2x80x94Oxe2x80x94C(O)xe2x80x94(CH2)2xe2x80x94X2, wherein X2 is carboxy or a derivative thereof. Particularly preferred meanings of L2xe2x80x2 are amino, carboxy and an activated carboxylic acid ester as mentioned above.
A further preferred embodiment of the invention relates to the use of a compound of formula (1), wherein L2 is a radical of formula (1a), L3 is xe2x80x94NHxe2x80x94, xe2x80x94C(O)Oxe2x80x94 orxe2x80x94C(O)NHxe2x80x94, h is 1, (spacer) is linear C2-C12-alkylene or xe2x80x94(C2-C3-alkylene)xe2x80x94Oxe2x80x94(CH2CH2O)18-160xe2x80x94(C2-C3-alkylene)xe2x80x94, and L2xe2x80x2 is carboxy, a carboxy derivative or a radical xe2x80x94Oxe2x80x94C(O)xe2x80x94(CH2)2xe2x80x94X2, wherein X2 is carboxy or an activated carboxylic acid ester as mentioned above.
Preferably, L1 is a group of formula 
g is 0, and L2 is carboxy, a carboxy derivative, or a radical of formula (1a) above, wherein the above-given meanings and preferences apply.
According to another preferred embodiment, L1 is a group xe2x80x94N3, g is 1 or preferably 0, R29 is methyl, methoxy, hydroxy or nitro, and L2 is amino, carboxy, a carboxy derivative, isocyanato, isothiocyanato or a radical of formula (1a) above, wherein the above-mentioned meanings and preferences apply, in particular amino.
The compounds of formula (1) may be applied to the material surface according to processes known per se. For example, the bulk material is immersed in a solution of a compound of formula (1), or a layer of a compound of formula (1) is first of all deposited on the bulk material surface to be modified, for example, by dipping, spraying, printing, spreading, pouring, rolling, spin coating or vacuum vapor deposition, with dipping or spraying being preferred. Most preferably, a solution comprising one or more different compounds of the formula (1) is sprayed onto the bulk material surface, which may be dry or preferably wet. The compound of formula (1) may be applied to the material surface in one cycle or in repeated cycles.
Suitable solvents useful as solvents of the compounds of formula (1) are, for example, water, C1-C4-alkanols such as methanol, ethanol or iso-propanol, nitrites such as acetonitrile, tetrahydrofuran (THF), aqueous solutions comprising an alkanol, THF or the like, ketones, for example acetone or methylethyl ketone, and also hydrocarbons, for example halogenated hydrocarbons such as methylene chloride or chloroform. The concentration of the compound of formula (1) in the spray solution depends on the specific compound used but is in general in the range of from 0.1 to 100 g/l, preferably 0.5 to 50 g/l, more preferably 0.5 to 25 g/l and in particular 1 to 10 g/l.
The fixation of the compounds of formula (1) on the bulk material surface then may be initiated, for example, by irradiation, particularly by irradiation with UV or visible light. Suitable light sources for the irradiation are known to the artisan and comprise for example mercury lamps, high pressure mercury lamps, xenon lamps, carbon arc lamps or sunlight. Sensitizers may be used to shift the irradiation wavelength. In addition, a suitable filter may be used to limit the irradiation to a specific wavelength range. Preferably, the bulk material surface to which the compound(s) of formula (1) have been previously applied, is irradiated with light of a wavelengthxe2x89xa7250 nm and preferablyxe2x89xa7300 nm. The time period of irradiation is not critical but is usually in the range of up to 30 minutes, preferably from 10 seconds to 10 minutes, and more preferably from 15 seconds to 5 minutes, and particularly preferably from 20 seconds to 1 minute. The irradiation may be carried out under ambient conditions or in an atmosphere of inert gas. Masks can be used for the generation of specific surface patterns of functional groups. Following the fixation reaction, any non-covalently bound compounds can be removed, for example by treatment, e.g. extraction, with suitable solvents, for example water, C1-C4-alkanols, water/C1-C4-alkanol mixtures or acetonitrile.
Depending on the desired concentration of functional groups L2 on the material surface, the above outlined process cycle, (i) contacting, i.e. spraying or dipping, the surface with the compound(s) of formula (1) and (ii) fixing the compound(s) of formula (1) on the surface, i.e. by irradiation, may be carried out once or, preferably, several times. For example, 1 to 100, preferably 1 to 50 and in particular 5 to 25, different layers of one or more compounds of formula (1) are added and fixed on the material surface.
A polymerization initiator according to step (a) is typically one that is initiating a radical polymerization of ethylenically unsaturated compounds. The radical polymerization may be induced thermally, or preferably by irradiation.
Initiators for the thermal polymerization are particularly functional initiators having an initiator part such as a peroxide, hydroperoxide, persulfate or azo group and in addition a functional group that is co-reactive with the functional groups L2 of the modified bulk material surface obtainable, for example, as described above or as disclosed in WO 99/57581. Suitable functional groups that are co-reactive with L2 are, for example, a carboxy, amino, hydroxy, epoxy or isocyanato group.
Initiators for the radiation-induced polymerization are particularly functional photoinitiators having a photoinitiator part and in addition a functional group that is co-reactive with the functional groups introduced to the bulk material surface by a plasma treatment according to step (i), or that is co-reactive with the functional groups L2 of the bulk material surface modified according step (ii). The photoinitiator part may belong to different types, for example to the thioxanthone type and preferably to the benzoin type. Suitable functional groups that are co-reactive with L2 are, for example, a carboxy, amino, hydroxy, epoxy or isocyanato group.
Preferred polymerization initiators for use in the present invention are the photoinitiators of formulae (l) and (la) as disclosed in U.S. Pat. No. 5,527,925, those of the formula (I) as disclosed in PCT application WO 96/20919, or those of formulae II and III including formulae IIa-IIy and IIIg as disclosed in EP-A-0281941, particularly formulae IIb, IIi, IIm, IIn, IIp, IIr, IIs, IIx and IIIg therein.
The polymerization initiator moieties are preferably derived from a functional photoinitiator of the formula 
wherein b1 and b2 are each 0, Z and Z1 are each bivalent xe2x80x94Oxe2x80x94, b3 is 0 or 1; R4 is methyl or phenyl, or both groups R4 together are pentamethylene; R5 is methyl or H; R3 is hydrogen; a is 1 and R2 is ethylene, or a is 0 and R2 is a direct bond; a1 is 0 or 1; and R1 is branched C6-C10-alkylene, phenylene or phenylene substituted by from 1 to 3 methyl groups, benzylene or benzylene substituted by from 1 to 3 methyl groups, cyclohexylene or cyclohexylene substituted by from 1 to 3 methyl groups, cyclohexyl-CH2xe2x80x94 or cyclohexyl-CH2xe2x80x94 substituted by from 1 to 3 methyl groups,
T is bivalent xe2x80x94Oxe2x80x94; Z2 is xe2x80x94Oxe2x80x94(CH2)yxe2x80x94 wherein y is an integer from 1 to 4 and the terminal CH2 group of which is linked to the adjacent T in formula (3c); R3 is H; R8 is methyl, allyl, tolylmethyl or benzyl, R9 is methyl, ethyl, benzyl or phenyl, or R8 and R9 together are pentamethylene, R10 and R11 are each independently of the other C1-C4-alkyl or R10 and R11 together are xe2x80x94CH2CH2OCH2CH2xe2x80x94, and R6 is branched C6-C10-alkylene, phenylene or phenylene substituted by from 1 to 3 methyl groups, benzylene or benzylene substituted by from 1 to 3 methyl groups, cyclohexylene or cyclohexylene substituted by from 1 to 3 methyl groups, cyclohexylene-CH2xe2x80x94 or cyclohexylene-CH2xe2x80x94 substituted by from 1 to 3 methyl groups.
Photoinitiators of formula (3a) and (3b) are particularly preferred.
Some examples of especially preferred functional photoinitiators are the compounds of formulae 
wherein R22 is a radical 
The reactions of radicals on the material surface that are derived from a compound of formula (1) having a carboxy, carboxy derivative, isocyanato or isothiocyanato group L2 with a functional polymerisation initiator having an amino or hydroxy group, or vice versa, are well-known in the art and may be carried out as desribed in textbooks of organic chemistry. For example, the reaction of a radical derived from a compound of formula (1), wherein L2 is an isocyanato or isothiocyanato group with an amino- or hydroxy-functionalized polymerisation initiator, or vice versa the reaction of an amino- or hydroxy group L2 with an isocyanato or isothiocyanato functionalized polymerisation initiator, may be carried out in an inert organic solvent such as an optionally halogenated hydrocarbon, for example petroleum ether, methylcyclohexane, toluene, chloroform, methylene chloride and the like, or an ether, for example diethyl ether, tetrahydrofurane, dioxane, or a more polar solvent such as DMSO, DMA, N-methylpyrrolidone or even a lower alcohol, at a temperature of from 0 to 100xc2x0 C., preferably from 0 to 50xc2x0 C. and particularly preferably at room temperature, optionally in the presence of a catalyst, for example a tertiary amine such as triethylamine or tri-n-butylamine, 1,4-diazabicyclooctane, or a tin compound such as dibutyltin dilaurate or tin dioctanoate. It is advantageous to carry out the above reactions under an inert atmosphere, for example under a nitrogen or argon atmosphere.
In case that the radicals on the material surface are derived from a compound of formula (1) having a carboxy group L2, the reaction of the carboxy group with an amino or hydroxy group functionalized photoinitiator, or vice versa the reaction of an amino or hydroxy group L2 with a carboxy functionalized polymerisation initiator, may be carried out under the conditions that are customary for ester or amide formation, for example in an aprotic medium at a temperature from about room temperature to about 100xc2x0 C. It is further preferred to carry out the esterification or amidation reaction in the presence of an activating agent, for example N-ethyl-Nxe2x80x2-(3-dimethylaminopropyl)carbodiimide (EDC), N-hydroxy succinimide (NHS), sulfo-N-hydroxy succinimide or N,Nxe2x80x2-dicyclohexyl carbodiimide (DCC) or in the presence of an o-(benztriazole)-uronium salt such as o-(benztriazol-1-y-)-N,N,N,N-tetramethyluronium hexafluorophosphate. Most preferably, the carboxy group L2 is previously converted to an activated ester using one of the above-mentioned activating agents, and the activated ester is then further reacted with the hydroxy or preferably amino groups of the surface.
In a preferred embodiment of the invention, L2 comprises amino, alkylamino or hydroxy, particularly amino, as reactive group and the co-reactive group of the polymerization initiator is an isocyanato group. A preferred polymerization initiator of this embodiment is a photoinitiator of the above formula (3b), (3c), (3d1), (3d2) or (3d3).
According to another preferred embodiment of the invention, L2 comprises carboxy, a carboxy derivative, isocyanato or isothiocyanato as reactive group, and the co-reactive group of the polymerization initiator is a hydroxy, amino, alkylamino or thiol group, particularly an amino group. A preferred polymerization initiator of this embodiment is a photoinitiator of the above formula (3a).
Hydrophilic ethylenically unsaturated macromonomers for graft polymerization from the bulk material surface according to step (b) of the process of the present invention are known, for example, from WO 99/57581. A suitable macromonomer is, for example of formula 
wherein R32 is hydrogen, C1-C6-alkyl or a radical xe2x80x94COORxe2x80x2;
R, Rxe2x80x2 and R32xe2x80x2 are each independently of the other hydrogen or C1-C6-alkyl;
A is a direct bond or is a radical of formula
xe2x80x94C(O)xe2x80x94(A1)nxe2x80x94Xxe2x80x94xe2x80x83xe2x80x83(5a) or
xe2x80x94(A2)mxe2x80x94NHxe2x80x94C(O)xe2x80x94Xxe2x80x94xe2x80x83xe2x80x83(5b) or
xe2x80x94(A2)mxe2x80x94Xxe2x80x94C(O)xe2x80x94xe2x80x83xe2x80x83(5c) or
xe2x80x94C(O)xe2x80x94NHxe2x80x94C(O)xe2x80x94Xxe2x80x94xe2x80x83xe2x80x83(5d) or
xe2x80x94C(O)xe2x80x94X1xe2x80x94(alk*)xe2x80x94Xxe2x80x94C(O)xe2x80x94xe2x80x83xe2x80x83(5e) or
A and R32, together with the adjacent double bond, are a radical of formula 
A1 is xe2x80x94Oxe2x80x94C2-C12-alkylene which is unsubstituted or substituted by hydroxy, or is xe2x80x94Oxe2x80x94C2-C12-alkylene-NHxe2x80x94C(O)xe2x80x94 or xe2x80x94Oxe2x80x94C2-C12-alkylene-Oxe2x80x94C(O)xe2x80x94NHxe2x80x94R33xe2x80x94NHxe2x80x94C(O)xe2x80x94 or xe2x80x94NHxe2x80x94(Alk*)xe2x80x94C(O)xe2x80x94, wherein (Alk*) is C1-C6-alkylene and R33 is linear or branched C1--C18-alkylene or unsubstituted or C1-C4-alkyl- or C1-C4-alkoxy-substituted C6--C10-arylene, C7-C18-aralkylene, C6-C10-arylene-C1-C2-alkylene-C6-C10-arylene, C3-C8-cycloalklene, C3-C8-cycloalklene-C1-C6-alkylene C3-C8-cycloalkylene-C1-C2-alkylene-C3-C8-cycloalklene or C1-C6-alkylene-C3-C8-cycloalkylene-C1-C6-alkylene;
A2 is C1-C8-alkylene; phenylene or benzylene;
m and n are each independently of the other the number 0 or 1;
X, X1 and Xxe2x80x2 are each independently of the other a bivalent group xe2x80x94Oxe2x80x94 or xe2x80x94NRxe2x80x3, wherein Rxe2x80x3 is hydrogen or C1-C6-alkyl;
(alk*) is C2-C12-alkylene;
and (oligomer) denotes
(i) the radical of a telomer of formula 
wherein (alk) is C2-C12-alkylene,
Q is a monovalent group that is suitable to act as a polymerization chain-reaction terminator,
p and q are each independently of another an integer from 0 to 350, wherein the total of (p+q) is an integer from 2 to 350,
and B and Bxe2x80x2 are each independently of the other a 1,2-ethylene radical derivable from a copolymerizable vinyl monomer by replacing the vinylic double bond by a single bond, at least one of the radicals B and Bxe2x80x2 being substituted by a hydrophilic substituent; or
(ii) the radical of an oligomer of the formula 
wherein R19 is hydrogen or unsubstituted or hydroxy-substituted C1-C12-alkyl, u is an integer from 2 to 250 and Qxe2x80x2 is a radical of a polymerization initiator; or
(iii) the radical of formula 
wherein R19, X and u are as defined above, or
(iv) the radical of an oligomer of formula 
wherein R20 and R20xe2x80x2 are each independently C1-C4-alkyl, Anxe2x88x92 is an anion, v is an integer from 2 to 250, and Qxe2x80x3 is a monovalent group that is suitable to act as a polymerization chain-reaction terminator; or
(v) the radical of an oligopeptide of formula
xe2x80x94(CHR21xe2x80x94C(O)xe2x80x94NH)txe2x80x94CHR21xe2x80x94COOHxe2x80x83xe2x80x83(6d) or
xe2x80x94CHR21xe2x80x94(NHxe2x80x94C(O)xe2x80x94CHR21)txe2x80x94NH2xe2x80x83xe2x80x83(6dxe2x80x2),
wherein R21 is hydrogen or C1-C4-alkyl which is unsubstituted or substituted by hydroxy, carboxy, carbamoyl, amino, phenyl, o-, m- or p-hydroxyphenyl, imidazolyl, indolyl or a radical xe2x80x94NHxe2x80x94C(xe2x95x90NH)xe2x80x94NH2 and t is an integer from 2 to 250, or the radical of an oligopeptide based on proline or hydroxyproline; or
(vi) the radical of a polyalkylene oxide of formula
xe2x80x94(alk**xe2x80x94O)zxe2x80x94[CH2xe2x80x94CH2xe2x80x94O]rxe2x80x94[CH2xe2x80x94CH(CH3)xe2x80x94O]6xe2x80x94R34xe2x80x83xe2x80x83(6e),
wherein R34 is hydrogen or C1-C24-alkyl, (alk**) is C2-C4-alkylene, z is 0 or 1, r and s are each independently an integer from 0 to 250 and the total of (r+s) is from 2 to 250; or
(vii) the radical of an oligosaccharide;
subject to the provisos that
A is not a direct bond if (oligomer) is a radical of formula (6a);
A is a radical of formula (5a), (5b) or (5d) or A and R32, together with the adjacent double bond, are a radical of formula (5f) if (oligomer) is a radical of formula (6b), (6c), (6d) or (6e) or is the radical of an oligosaccharide;
A is a direct bond if (oligomer) is a radical of formula (6bxe2x80x2); and
A is a radical of formula (5c) or (5e) if (oligomer) is a radical of formula (6dxe2x80x2).
The following preferences apply to the variables contained in the definition of the macromonomer of formula (4):
Rxe2x80x2 is preferably hydrogen or C1-C4-alkyl, more preferably hydrogen or C1-C2-alkyl and particularly preferably hydrogen.
R32 is preferably hydrogen, methyl or carboxyl, and particularly preferably hydrogen.
R is preferably hydrogen or methyl.
X is preferably a bivalent group xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94. X is particularly preferably the group xe2x80x94NHxe2x80x94 if (oligomer) is a radical of formula (6a); (6c) or (6d), and is particularly preferably the group xe2x80x94Oxe2x80x94 if (oligomer) is a radical of formula (6b) or (6e) or is the radical of an oligosaccharide. Xxe2x80x2 is preferably xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94 and more preferably xe2x80x94NHxe2x80x94. X1 is preferably xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94.
The radical R33 has a symmetrical or, preferably, an asymmetrical structure. R33 is preferably linear or branched C6-C10alkylene; cyclohexylene-methylene or cyclohexylene-methylene cyclohexylene each unsubstituted or substituted in the cyclohexyl moiety by from 1 to 3 methyl groups; or phenylene or phenylene-methylene-phenylene each unsubstituted or substituted in the phenyl moiety by methyl. The bivalent radical R33 is derived preferably from a diisocyanate and most preferably from a diisocyanate selected from the group isophorone diisocyanate (IPDI), toluylene-2,4-diisocyanate (TDI), 4,4xe2x80x2-methylenebis(cyclohexyl iso-cyanate), 1,6-diisocyanato-2,2,4-trimethyl-n-hexane (TMDI), methylenebis(phenyl isocyanate), methylenebis(cyclohexyl-4-isocyanate) and hexamethylene diisocyanate (HMDI).
Preferred meanings of A1 are unsubstituted or hydroxy-substituted xe2x80x94Oxe2x80x94C2-C8-alkylene or a radical xe2x80x94Oxe2x80x94C2-C6-alkylene-NHxe2x80x94C(O)xe2x80x94 and particularly xe2x80x94Oxe2x80x94(CH2)2-4xe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94 or a radical xe2x80x94Oxe2x80x94(CH2)2-4xe2x80x94NHxe2x80x94C(O)xe2x80x94. A particularly preferred meaning of A1 is the radical xe2x80x94Oxe2x80x94(CH2)2xe2x80x94NHxe2x80x94C(O)xe2x80x94.
A2 is preferably C1-C6-alkylene, phenylene or benzylene, more preferably C1-C4-alkylene and even more preferably C1-C2-alkylene. n is an integer of 0 or preferably 1. m is preferably an integer of 1R32xe2x80x2 is preferably hydrogen or methyl and particularly preferably hydrogen. In case that (oligomer) is a radical of formula (6a), (6b), (6c), (6d) or (6e) or is the radical of an oligosaccharide, is A preferably a radical of formula (5a) or (5b) and particularly preferably a radical of formula (5a), wherein the above given meanings and preferences apply for the variables contained therein.
A preferred group of hydrophilic macromonomers according to the invention comprises compounds of the above formula (4), wherein R is hydrogen or methyl, R32 is hydrogen, methyl or carboxyl, R32xe2x80x2 is hydrogen, A is a radical of the formula (5a) or (5b) and (oligomer) is a radical of formula (6a), (6b), (6c), (6d) or (6e) or is the radical of an oligosaccharide. An even more preferred group of hydrophilic macromonomers comprises compounds of the above formula (4), wherein R is hydrogen or methyl, R32 and R32xe2x80x2 are each hydrogen, A is a radical of the formula (5a) and (oligomer) is a radical of formula (6a). A further group of preferred macromonomers comprises compounds of formula (4), wherein A is a radical of formula (5e) above and (oligomer) is a radical of formula (6a).
(Alk*) is preferably methylene, ethylene or 1,1-dimethyl-methylene, in particular a radical xe2x80x94CH2xe2x80x94 or xe2x80x94C(CH3)2xe2x80x94. (alk) and (alk*) are each independently preferably C2-C8-alkylene, more preferably C2-C6-alkylene, even more preferably C2-C4-alkylene and particularly preferably 1,2-ethylene. The alkylene radicals (alk) and (alk*) may be branched or preferably linear alkylene radicals.
Q is for example hydrogen.
The total of (p+q) is preferably an integer from 2 to 150, more preferably from 5 to 100, even more preferably from 5 to 75 and particularly preferably from 10 to 50. In a preferred embodiment of the invention q is 0 and p is an integer from 2 to 250, preferably from 2 to 150, more preferably from 5 to 100, even more preferably from 5 to 75 and particularly preferably from 10 to 50.
Suitable hydrophilic substituents of the radicals B or Bxe2x80x2 are those described in WO 99/57581 on pages 16 to 24.
A group of preferred non-ionic substituents of B or Bxe2x80x2 comprises C1-C2-alkyl, which is unsubstituted or substituted by xe2x80x94OH or xe2x80x94NR23R23xe2x80x2, wherein R23 and R23xe2x80x2 are each independently of the other hydrogen or C1-C2-alkyl; a radical xe2x80x94COOY wherein Y is C1-C4-alkyl; C2-C4-alkyl which is substituted by xe2x80x94OH, xe2x80x94NR23R23xe2x80x2 wherein R23 and R23xe2x80x2 are each independently of another hydrogen or C1-C2-alkyl, or Y is a radical xe2x80x94C2-C4-alkylene-NHxe2x80x94C(O)xe2x80x94Oxe2x80x94G wherein xe2x80x94Oxe2x80x94G is the radical of a saccharide; a radical xe2x80x94C(O)xe2x80x94NY1Y2, wherein Y1 and Y2 are each independently of the other hydrogen or C1-C6-alkyl which is unsubstituted or substituted by hydroxy, or Y1 and Y2 together with the adjacent N-atom form a heterocyclic 6-membered ring having no further heteroatom or having one further N- or O-atom; a radical xe2x80x94OY3, wherein Y3 is hydrogen, C1-C4-alkyl which is unsubstituted or substituted by xe2x80x94NH2 or xe2x80x94N(C1-C2-alkyl)2, or is a group xe2x80x94C(O)C1-C2-alkyl; or a 5- or 6-membered heteroaromatic or heteroaliphatic radical having one N-atom and in addition no further heteroatom or an additional N- , O- or S-heteroatom, or a 5 to 7-membered lactame.
A group of more preferred non-ionic substituents of B or Bxe2x80x2 comprises a radical xe2x80x94COOY, wherein Y is C1-C2-alkyl, C2-C3-alkyl, which is substituted by hydroxy, amino or N,N-di-C1-C2-alkylamino, or is a radical xe2x80x94C2-C4-alkylene-NHxe2x80x94C(O)xe2x80x94Oxe2x80x94G wherein xe2x80x94Oxe2x80x94G is the radical of trehalose; a radical xe2x80x94COxe2x80x94NY1Y2, wherein Y1 and Y2 are each independently of the other hydrogen or C1-C4-alkyl which is unsubstituted or substituted by hydroxy, or Y1 and Y2 together with the adjacent N-atom form a Nxe2x80x94C1-C2-alkylpiperazino or morpholino ring; or a heterocyclic radical selected from the group consisting of N-pyrrolidonyl, 2- or 4-pyridinyl, 2-methylpyridin-5-yl, 2-, 3- oder 4-hydroxypyridinyl, N-xcex5-caprolactamyl, N-imidazolyl, 2-methylimidazol-1-yl, N-morpholinyl and 4-N-methylpiperazin-1-yl.
A particularly preferred group of non-ionic substituents of B or Bxe2x80x2 comprises the radicals xe2x80x94CONH2, xe2x80x94CON(CH3)2, 
xe2x80x94CONHxe2x80x94(CH2)2xe2x80x94OH, xe2x80x94COOxe2x80x94(CH2)2xe2x80x94N(CH3)2, and xe2x80x94COO(CH2)2-4xe2x80x94NHC(O)xe2x80x94Oxe2x80x94G wherein xe2x80x94Oxe2x80x94G is the radical of trehalose.
Particularly preferred anionic substituents of B or Bxe2x80x2 are xe2x80x94COOH, xe2x80x94SO3H, o-, m- or p-sulfophenyl, o-, m- or p-sulfomethylphenyl or a radical xe2x80x94CONY5Y6 wherein Y5 is C2-C4-alkyl substituted by sulfo, and Y6 is hydrogen.
A preferred cationic substituent of B or Bxe2x80x2 is a radical xe2x80x94C(O)OY7 wherein Y7 is C2-C4-alkyl, which is substituted by xe2x80x94N(C1-C2-alkyl)3+Anxe2x88x92 and is further substituted by hydroxy, and Anxe2x88x92 is an anion, for example the radical xe2x80x94C(O)Oxe2x80x94CH2xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94N(CH3)3+Anxe2x88x92.
A preferred group of zwitter-ionic substituents xe2x80x94R24xe2x80x94Zw corresponds to the formula
xe2x80x94C(O)Oxe2x80x94(alkxe2x80x2xe2x80x3)xe2x80x94N(R23)2+xe2x80x94(alkxe2x80x2)xe2x80x94Anxe2x88x92 or 
xe2x80x94C(O)Oxe2x80x94(alkxe2x80x3)xe2x80x94Oxe2x80x94PO2xe2x80x94(O)0-1xe2x80x94(alkxe2x80x2xe2x80x3)xe2x80x94N(R23)3+
wherein R23 is hydrogen or C1-C6-alkyl; An+ is an anionic group xe2x80x94COOxe2x88x92, xe2x80x94SO3xe2x88x92 or xe2x80x94OPO3Hxe2x88x92, preferably xe2x80x94COOxe2x88x92 or xe2x80x94SO3xe2x88x92 and most preferably xe2x80x94SO3xe2x88x92, alkxe2x80x2 is C1-C12-alkylene, (alkxe2x80x3) is C2-C24-alkylene which is unsubstituted or substituted by a radical xe2x80x94OY8, Y8 is hydrogen or the acyl radical of a carboxylic acid, and (alkxe2x80x2xe2x80x3) is C2-C8-alkylene.
(alkxe2x80x2) is preferably C2-C8-alkylene, more preferably C2-C6-alkylene and most preferably C2-C4-alkylene.(alkxe2x80x3) is preferably C2-C12-alkylene, more preferably C2-C6-alkylene and particularly preferably C2-C3-alkylene which is in each case unsubstituted or substituted by hydroxy or by a radical xe2x80x94OY8. (alkxe2x80x2xe2x80x3) is preferably C2-C4-alkylene and more preferably C2-C3-alkylene R23 is hydrogen or C1-C4-alkyl, more preferably methyl or ethyl and particularly preferably methyl. A preferred zwitterionic substituent of B or Bxe2x80x2 is of formula
xe2x80x94C(O)Oxe2x80x94CH2xe2x80x94CH(OY8)xe2x80x94CH2xe2x80x94Oxe2x80x94PO2xe2x88x92xe2x80x94(CH2)2xe2x80x94N(CH3)3+
wherein Y8 is hydrogen or the acyl radical of a higher fatty acid.
B denotes for example a radical of formula 
wherein R25 is hydrogen or C1-C4-alkyl, preferably hydrogen or methyl; R26 is a hydrophilic substituent, wherein the above given meanings and preferences apply; R27 is C1-C4-alkyl, phenyl or a radical xe2x80x94C(O)OY9, wherein Y9 is hydrogen or unsubstituted or hydroxy-substituted C1-C4-alkyl; and R28 is a radical xe2x80x94C(O)Y9xe2x80x2 or xe2x80x94CH2xe2x80x94C(O)OY9xe2x80x2 wherein Y9xe2x80x2 independently has the meaning of Y9.
R27 is preferably C1-C2-alkyl, phenyl or a group xe2x80x94C(O)OY9. R28 is preferably a group xe2x80x94C(O)OY9xe2x80x2 or xe2x80x94CH2xe2x80x94C(O)OY9xe2x80x2 wherein Y9 and Y9xe2x80x2 are each independently of the other hydrogen, C1-C2-alkyl or hydroxy-C1-C2-alkyl. Particularly preferred xe2x80x94CHR27xe2x80x94CHR28xe2x80x94 units according to the invention are those wherein R27 is methyl or a group xe2x80x94C(O)OY9 and R28 is a group xe2x80x94C(O)OY9xe2x80x2 or xe2x80x94CH2xe2x80x94C(O)OY9xe2x80x2 wherein Y9 and Y9xe2x80x2 are each hydrogen, C1-C2-alkyl or hydroxy-C1-C2-alkyl.
Bxe2x80x2 independently may have one of the meanings given above for B.
If (oligomer) is a radical of formula (6a), the radical xe2x80x94(alk)xe2x80x94Sxe2x80x94[B]pxe2x80x94[Bxe2x80x2]qxe2x80x94Q preferably denotes a radical of formula 
even more preferably of the formula 
wherein for R25, R26, Q, p and q the above-given meanings and preferences apply, for R25xe2x80x2 independently the meanings and preferences given before for R25 apply, and for R26xe2x80x2 independently the meanings and preferences given before for R26 apply.
A preferred group of suitable hydrophilic macromonomers according to step (b) of the invention comprises compounds of formula 
wherein R is hydrogen or methyl, A1 is xe2x80x94Oxe2x80x94(CH2)24xe2x80x94, xe2x80x94Oxe2x80x94CH2xe2x80x94CH(OH)xe2x80x94CH2xe2x80x94 or a radical xe2x80x94Oxe2x80x94(CH2)2-4xe2x80x94NHxe2x80x94C(O)xe2x80x94, X is xe2x80x94Oxe2x80x94 or xe2x80x94NHxe2x80x94, (alk) is C2-C4-alkylene, Q is a monovalent group that is suitable to act as a polymerization chain-reaction terminator, p is an integer from 5 to 50, R25 and R25xe2x80x2 are each independently of the other hydrogen or methyl, and for R26 and R26xe2x80x2 each independently the above given meanings and preferences apply.
A particularly preferred embodiment of the invention relates to hydrophilic macromonomers of the formula 
wherein for R, R25, R26, Q, (alk) and p the above-given meanings and preferences apply. A particularly preferred group of hydrophilic macromonomers are compounds of the above formula (4b) wherein R is hydrogen or methyl, (alk) is C2-C4-alkylene, R25 is hydrogen or methyl, p is an integer of 5 to 50, Q is as defined before, and for R26 the above given meanings and preferences apply; in particular R26 of this embodiment is a radical xe2x80x94CONH2, xe2x80x94CON(CH3)2 or 
If (oligomer) is a radical (ii) of formula (6b), Qxe2x80x2 in formula (6b) is for example C1-C12-alkyl, phenyl or benzyl, preferably C1-C2-alkyl or benzyl and in particular methyl. R19 is preferably unsubstituted or hydroxy-substituted C1-C4-alkyl and in particular methyl. u is preferably an integer from 2 to 150, more preferably from 5 to 100, even more preferably from 5 to 75 and particularly preferably from 10 to 50.
If (oligomer) is a radical of formula (6bxe2x80x2), the above given meanings and preferences apply for the variables R19 and u contained therein. X in formula (6bxe2x80x2) is preferably hydroxy or amino.
If (oligomer) denotes a radical (iv) of formula (6c), R20 and R20xe2x80x2 are each preferably ethyl or in particular methyl; v is preferably an integer from 2 to 150, more preferably from 5 to 100, even more preferably from 5 to 75 and particularly preferably from 10 to 50; Qxe2x80x3 is for example hydrogen; and Anxe2x88x92 is as defined before.
If (oligomer) denotes an oligopeptide radical (v) of formula (6d) or 6dxe2x80x2), R21 is for example hydrogen, methyl, hydroxymethyl, carboxymethyl, 1-hydroxyethyl, 2-carboxyethyl, isopropyl, n-, sec. or iso-butyl, 4-amino-n-butyl, benzyl, p-hydroxybenzyl, imidazolylmethyl, indolylmethyl or a radical xe2x80x94(CH2)3xe2x80x94NHxe2x80x94C(xe2x95x90NH)xe2x80x94NH2. t is preferably an integer from 2 to 150, more preferably from 5 to 100, even more preferably from 5 to 75 and particularly preferably from 10 to 50.
If (oligomer) denotes a polyoxyalkylene radical (vi) of formula (6e), R34 is preferably hydrogen or C1-C18-alkyl, more preferably hydrogen or C1-C12-alkyl, even more preferably hydrogen, methyl or ethyl, and particularly preferably hydrogen or methyl. (alk **) is preferably a C2-C3-alkylene radical. z is preferably 0. r and s are each independently preferably an integer from 0 to 100 wherein the total of (r+s) is 5 to 100. r and s are each independently more preferably an integer from 0 to 50 wherein the total of (r+s) is 8 to 50. In a particularly preferred embodiment of the polyoxyalkylene radicals (oligomer), r is an integer from 8 to 50 and particularly 9 to 25, and s is 0. (oligomer) as the radical of an oligosaccharide (vii) may be, for example, a di- or polysaccharide including carbohydrate containing fragments from a biopolymer. Examples are the radical of a cyclodextrin, trehalose, cellobiose, maltotriose, maltohexaose, chitohexaose or a starch, hyaluronic acid, deacetylated hyaluronic acid, chitosan, agarose, chitin 50, amylose, glucan, heparin, xylan, pectin, galactan, glycosaminoglycan, mucin, dextran, aminated dextran, cellulose, hydroxyalkylcellulose or carboxyalkylcellulose oligomer, each of which with a molecular weight average weight of, for example, up to 25,000 Da, preferably up to 10,000 Da. Preferably the oligosaccharide according to (vii) is the radical of a cyclodextrin with a maximum of 8 sugar units.
Formulae (6a), (6axe2x80x2) or (6e) are to be understood as a statistic description of the respective oligomeric radicals, that is to say, the orientation of the monomers and the sequence of the monomers (in case of copolymers) are not fixed in any way by said formulae. The arrangement of B and Bxe2x80x2 in formula (6a) or of the ethyleneoxide and propyleneoxide units in formula (6e) thus in each case may be random or blockwise.
The weight average molecular weight of the hydrophilic macromonomer according to step (b) depends principally on the desired properties and is for example from 300 to 25000 Da, preferably from 300 to 12,000 Da, more preferably from 300 to 8000 Da, even more preferably from 300 to 5000 Da, and particularly preferably from 500 to 4000 Da.
The macromonomers of formula (4) may be prepared by methods known per se, as described in, for example, WO 99/57581.
A wide variety of structurally different polymers are suitable for use in step (b) of the present invention subject to the condition that said polymers lack polymerizable ethylenically unsaturated groups and are hydrophilic and biocompatible. Suitable biocompatible hydrophilic polymers comprise, for example, biopolymers, modified biopolymers and synthetic polymers.
The weight average molecular weight Mw of biocompatible hydrophilic polymers according to step (b) depends principally on the desired properties and is from 1000 to 5,000,000 Da, preferably from 10,000 to 1,000,000 Da, and particularly preferably from 100,000 to 500,000 Da.
Examples of suitable biopolymers are polysaccharides, for example, hyaluronic acid, chondriotin sulfate, dextran, 1,3-glucan, fucoidan; glycoproteins, for example, mucin, fibronectin; glucosamines, for example chitin, chitosan, heparin; polypeptides, for example, lysozyme, collagen; proteins, for example albumen, immunoglobulines.
Examples of suitable modified biopolymers are, for example, carboxyalkylcellulose, for example carboxymethylcellulose, carboxyalkylchitin, carboxyalkylchitosan.
Examples of suitable synthetic polymers are bis-aminoalkylene-polyalkylefle glycols of various average molecular weights, for example JEFFAMINE(copyright) polyoxyalkylene amines; polyethyleneglycols, poly(hydroxyethyl methacrylate (poly-HEMA), high molecular weight, crosslinked, acrylic acid based polymers, for example, Carbopol(copyright) polymers (high molecular weight homo- and copolymers of acrylic acid crosslinked with a polyalkenyl polyether) and NOVEON(copyright) Polycarbophils (polymers of acrylic acid crosslinked with divinyl alcohol. polyacrylamide, polyvinylpyrrolidone, polyvinyl alcohol.
Preferred biocompatible hydrophilic polymers are highly branched and/or possess molecular weights  greater than 40,000 Da. Especially preferred are hyarulonic acid, dextran, heparin, chondriotin sulfate, mucin, polyvinylpyrrolidone or a NOVEON(copyright) Polycarbophil or Carbopol(copyright) polymer.
The biocompatible hydrophilic polymer is not covalently bonded to the polymer chains of the macromonomer. Chain entanglement, hydrogen bonds, Van der Waals forces and charge interactions are among the most important interactions between the hydrophilic macromonomers grafted from the bulk material and the biocompatible hydrophilic polymer. These forces stabilize the entangled biocompatible hydrophilic polymer and prevent it""s rapid leaching from the interpenetration mixture under physiological conditions. Preferably, the biocompatible hydrophilic polymers contribute significantly to specific advantageous features of the s-IPN-structured coating. Among those are for example: lubrication, water retention and stabilization of aqueous surface layers, biocompatibility, reversible attraction of biomolecules (e.g. mucins) from biological fluids, prevention of irreversible deposition of proteins, lipids and salts and inhibition of microbial adhesion. Controlled low rate leaching of entangled biocompatible hydrophilic polymers out of the contact lens coatings can enhance lubricity and comfort, and in addition can favour a continuous renewal of the lens surface.
Additional components can be included within the s-IPN. They can either be uncrosslinked polymers, oligomers or low molecular weight components with their leaching rates from the s-IPN naturally increasing with descreasing molecular masses. An additional component is preferably a bioactive material or a bioactive polymer. In a particular embodiment of the invention an additional component can be an enzyme, an antibody, an antimicrobial peptide, a polyquat or a growth factor. It is characteristic for additional components that they slowly release from the coating under physiological conditions.
The practical use of devices and articles carrying coatings according to the disclosed technology can be seen in technical, in biological and in environmental systems. Applications in the biomedical field are preferred: in particular, coatings for ophthalmic devices and implants, such as contact lenses, ocular drug delivery systems, intraocular lenses and artificial corneas.
In addition, s-IPN coatings of the present invention are outstanding with regard to their capability of lubricating contact lens surfaces and thus reducing the blinking frequency and the overall wearing comfort of contact lens users. By lubricating the cornea surface (via leachables) contact lens coatings of the present invention can improve the on-eye mobility of contact lens. All this is of particular importance with regard to extended wear contact lenses. These advantageous effects can be caused or be enhanced by leaching of B and/or C. The surface coatings of the invention can also be applied to ophthalmic implants. In technical applications coatings of the present invention can prevent befouling of separation membranes and can reduce friction, calcification, scale and drag phenomena in hydrodynamic systems.
The mixture of hydrophilic macromonomers and biocompatible hydrophilic polymer may be applied to the initiator-modified material according to processes known per se. For example, the material comprising the covalently bound polymerisation initiator is immersed in a solution of the macromonomer and biocompatible hydrophilic polymer, or a layer of said solution is first of all deposited on the modified material surface, for example, by dipping, spraying, spreading, knife coating, pouring, rolling, spin coating or vacuum vapor deposition. Suitable solvents, if used in the polymerization process, are, for example, water or dipolar aprotic solvents such as, for example, acetonitrile. The polymerization of the hydrophilic macromonomer on the material surface then may be initiated , for example, thermally by the action of heat or preferably by irradiation, particularly by UV radiation. Suitable light sources for the irradiation are known to the artisan and comprise for example mercury lamps, high-pressure mercury lamps, xenon lamps, carbon arc lamps or sunlight. The time period of irradiation may depend for example on the desired properties of the resulting composite material but is usually in the range of up to 30 minutes, preferably from 10 seconds to 10 minutes, and particularly preferably from 0.5 to 5 minutes. It is advantageous to carry out the irradiation in an atmosphere of inert gas.
The coated material obtained according to the invention may be purified afterwards in a manner known per se, for example by washing or extraction with a suitable solvent such as water.
By means of process step (b) of the above-described coating process, the hydrophilic macromonomers may be grafted to the material surface with formation of a coating having, for example, a so-called bottle brush-type structure (BBT) composed of tethered xe2x80x9chairyxe2x80x9d chains. Such BBT structures in one embodiment comprise a long hydrophilic or hydrophobic backbone, which carries relatively densely, packed comparatively short hydrophilic side chains (called primary bottle brushes). Another embodiment relates to secondary bottle brushes which are characterized in that the hydrophilic side chains themselves carry densely packed hydrophilic xe2x80x9csecondaryxe2x80x9d side chains. Polymeric coatings of said primary and secondary BBT structures to a certain extent mimic highly water-retaining structures occurring in the human body, for example in cartilage or mucosal tissue.
A further embodiment of the invention relates to a material that is coated by the process of the invention.
The material that is coated by the process of the invention is, for example, an organic bulk material, preferably a biomedical device, e.g. an ophthalmic device, preferably a contact lens including both hard and particularly soft contact lenses, an intraocular lens or artificial cornea. Further examples are materials useful for example as wound healing dressings, eye bandages, materials for the sustained release of an active compound such as a drug delivery patch, moldings that can be used in surgery, such as heart valves, vascular grafts, catheters, artificial organs, encapsulated biologic implants, e.g. pancreatic islets, materials for prostheses such as bone substitutes, or moldings for diagnostics, membranes or biomedical instruments or apparatus.
The biomedical devices, e.g. ophthalmic devices obtained according to the invention have a variety of unexpected advantages over those of the prior art which make those devices very suitable for practical purposes, e.g. as contact lens for extended wear or intraocular lens. For example, they do have a high surface wettability, which can be demonstrated by their contact angles, their water retention and their water-film break up time or tear film break up time (TBUT).
The TBUT plays a particularly important role in the field of ophthalmic devices such as contact lenses. Thus the facile movement of an eyelid over a contact lens has proven important for the comfort of the wearer; this sliding motion is facilitated by the presence of a continuous layer of tear fluid on the contact lens, a layer that lubricates the tissue/lens interface. However, clinical tests have shown that currently available contact lenses partially dry out between blinks, thus increasing friction between eyelid and the lens. The increased friction results in soreness of the eyes and reduced movement of the contact lenses. Now it has become feasible to considerably increase the TBUT of commercial contact lenses such as, for example, those made of nelfilcon A, vifilcon A or lotrafilcon A polymer, by applying a surface coating according to the invention. On the base curve of a contact lens, the pronounced lubricity of the coating facilitates the on-eye lens movement, which is essential for extended wear of contact lenses. Moreover, the materials obtained by the process of the invention provide additional effects being essential for lenses for extended wear, such as an increased thickness of the pre-lens tear film which contributes substantially to low microbial adhesion and resistance to deposit formation. Due to the very slow release of the biocompatible hydrophilic polymer the surface coatings according to the present invention are extremely soft and lubricious. Biomedical articles such as in particular contact lenses coated by the process of the invention show a superior wearing comfort including improvements with respect to late day dryness and long term (overnight) wear. The novel surface coatings moreover interact in a reversible manner with ocular mucus, which contributes to the improved wearing comfort.
In addition, biomedical devices, e.g. ophthalmic devices such as contact lenses, coated by the process of the invention, have a very pronounced biocompatibility combined with good mechanical properties. For example, the devices are blood compatible and have good tissue integration. In addition, there are generally no adverse eye effects observed, while the adsorption of proteins or lipids are low, also the salt deposit formation is lower than with conventional contact lenses. Generally, there is low fouling, low microbial adhesion and low bio erosion while good mechanical properties can be for example found in a low friction coefficient and low abrasion properties. Moreover, the dimensional stability of the materials obtained according to the invention is excellent. In addition, the attachment of a hydrophilic surface coating at a given bulk material according to the invention does not affect its visual transparency.
In summary, the ophthalmic devices obtained by the process of the invention, such as contact lenses and artificial cornea, provide a combination of low spoilation with respect to cell debris, cosmetics, dust or dirt, solvent vapors or chemicals, with a high comfort for the patient wearing such ophthalmic devices in view of the soft hydrogel surface which for example provides a very good on-eye movement of the ophthalmic device.
Biomedical devices such as renal dialysis membranes, blood storage bags, pacemaker leads or vascular grafts coated by the process of the invention resist fouling by proteins by virtue of the continuous layer of bound water, thus reducing the rate and extent of thrombosis. Blood-contacting devices fabricated according to the present invention are therefore haemocompatible and biocompatible.
In the examples, if not indicated otherwise, amounts are amounts by weight, temperatures are given in degrees Celsius. Tear break-up time values in general relate to the pre-lens tear film non-invasive break-up time (PLTF-NIBUT) that is determined following the procedure published by M. Guillon et al., Ophthal. Physiol. Opt. 9, 355-359 (1989) or M. Guillon et al., Optometry and Vision Science 74, 273-279 (1997). Average advancing and receding water contact angles of coated and non-coated lenses are determined with the dynamic Wilhelmy method using a Krxc3xcss K-12 instrument (Krxc3xcss GmbH, Hamburg, Germany). Wetting force on the solid is measured as the solid is immersed in or withdrawn from a liquid of known surface tension.